19-Nor-vitamin D compounds

ABSTRACT

A 19-nor intermediate compound of the formula ##STR1## where R is the sidechain of a vitamin D derivative and where X 1  and X 2  are hydrogen or a hydroxy protecting group. The compounds are used in the preparation of 19-nor-vitamin D end products.

This invention was made with United States Government support awarded bythe National Institutes of Health (NIH), Grant No. DK-14881. The UnitedStates Government has certain rights in this invention.

This application is a divisional of application Ser. No. 08/410,858filed Mar. 27, 1995, now U.S. Pat. No. 5,525,745, which in turn is adivisional of Ser. No. 08/302,399 filed Sep. 8, 1994, now U.S. Pat. No.5,430,196, which in turn is a continuation of Ser. No. 07/926,829, filedAug. 7, 1992 now abandoned.

BACKGROUND OF THE INVENTION

This invention was made in the course of research supported by fundsfrom from the U.S. government. invention relates to vitamin D compounds,specifically to a new process for the preparation of1α-hydroxy-19-nor-vitamin D analogs and to novel syntheticintermediates.

19-Nor-vitamin D compounds are vitamin D analogs in which the ring Aexocyclie methylene group (carbon 19) typical of all vitamin D compoundshas been removed and replaced by two hydrogen atoms. Specifically, thesecompounds exhibit a selective activity profile with high potency ininducing cellular differentiation, and minimal bone calcificationactivity. Such a differential activity profile renders these compoundsuseful for the treatment of malignancies, or the treatment of variousskin disorders. Two different methods of synthesis of these19-nor-vitamin D analogs have been described (Perlman et al. TetrahedronLetters 31, 1823 (1990); Perlman et al. Tetrahedron Letters 32, 7663(1991), DeLuca et al., U.S. Pat. No. 5,086,191).

A new method for the synthesis of such analogs has now been developed dis disclosed herein. The method takes advantage of the finding ofWalborsky and Wust (J. Am. Chem. Soc. 104, 5807, 1982) that1,4-diol-2-ene compounds can be reduced by low-valent titanium reagentsto 1,3-dienes. Solladie and Hutt (J. Org. Chem. 52, 3560, 1987) haveexploited this type of reduction for the preparagon ofdihydrotachysterol and dihydrotamin D compounds.

SUMMARY OF THE INVENTION

For the synthesis of 1α-hydroxy-19-nor-vitamin D compounds, the newmethod comprises, (a) the construction of a 5,8-diol-6-yne system,joining the ring-A and ring-C/D portions of the desired product asrepresented by general structure III below; (b) the partial reduction ofthe acetylenic linkage to obtain a 5,8-diol-6-ene system as depicted bygeneral structure IV; and (c) the reductive removal of the 5,8-oxygenfunctions to generate the required 5,7-diene product (compound V, below)from which the desired 7-trans(7E)-isomer (compound Va) is puritheddirectly, or after optional double bond isomerization of the7-cis(7Z)-isomer employing a novel thiophenol-promoted isomerizationstep.

DETAILED DESCRIPTION OF THE INVENTION

The first step of the new synthesis of 19-nor-vitamin D derivativesinvolves the condensation of an acetylenic derivative of generalstructure I (containing the C/D-ring portion of the desired product)with a cyclic dihydroxy ketone of general structure II (representing theA-ring of the desired product).

In these structures, X₁, X₂, and X₃, which may be the same or different,may represent hydrogen or a hydroxy-protecting group, but preferably,for optimal use in the present process, they each represent ahydroxy-protecting group. For X₁ and X₂ preferred hydroxy-protectinggroups are those that are base-stable, but readily removable whendesired. Suitable groups are, for example, alkylsilyl- or alkylarylsilylgroups (herein after referred to simply as "silyl" groups, e.g.trimethylsilyl, triethylsilyl, dibutylmethylsilyl, diphenylmethylsilyl,phenyldimethylsilyl, diphenyl-t-butylsilyl, etc.) or alkoxyalkyl groups(e.g. methoxymethyl-, ethoxymethyl, methoxyethoxymethyl, etc., ortetrahydropyranyl, tetrahydrofuranyl groups). In the case of X₃,suitable protecting groups are the silyl groups and the alkoxyalkylgroups already mentioned, as well as alkyl groups from 1 to 6 carbons(methyl, ethyl, propyl, isopropyl, etc.). The group R in compound Irepresents a side chain group as further defined below. ##STR2##

Cyclohexanone derivatives of general structure II are known (Perlman etal. Tetrahedron Letters 32, 7,663 (1991); acetylenic intermediates ofstructure I can be prepared by reaction of the correspondingperhydrindene ketones, (C/D-ring-ketones) having the general structureIa, below, with an acetylenic Grignard reagent and subsequent hydroxyprotection (Solladie and Hutt, J. Org. Chem. 52, 3560 (1987). Therequired substituted perhydrindene ketones bearing a diverse range ofside chain groups (R) are known or can be prepared by known methods[e.g. Perlman et al., Tetrahedron Letters 32, 7663 (1991); Wilson etal., J. Org. Chem. 57, 2007 (1992); Curtin and Okamura, J. Am. Chem.Soc. 113., 6958 (1991); Baggiolini et al., J. Org. Chem. 51, 3098(1986); Kiegiel et al., Tetrahedron Letters 32, 6057 (1991); Einhorn etal., Synthesis, p. 787 (1989); Mascarenas et al. Tetrahedron Letters 32,2813 (1991); Shiiuey et al. J. Org. Chem. 55, 243 (1990); Hatekeyama etal. J.C.S. Chem. Comm. 1030 (1989)]. ##STR3##

The coupling reaction between the acetylenic intermediate of structure Iand the cyclohexanone derivative of structure II requires the conversionof the acetylenic compound to a metal acetylide, which is then allowedto react with the ketone. Thus, the reaction is conducted in an organicsolvent, such as an ether or hydrocarbon solvent, at low temperature,and in the presence of a strong organic base (e.g. an alkyl lithium,alkyl lithium aide or analogous strong base). The standard conditionsfor achieving the condensation of an acetylenic compound with a ketone(e.g. as done in the work of Solladie, supra), typically comprise thetreatment of the acetylenic compound with the strong base to produce thelithium acetylide, followed by reaction of the acetylide with the ketonederivative. It was found, however, that such known conditions did notserve for the present synthesis, where the ketone derivative ofstructure II contains two protected hydroxy groups, which proved to beprone to elimination, yielding undesired products. This difficulty wasovercome by conducting the above condensation reaction in the presenceof both a strong base (alkyllithium, dialkyllithium amide, etc.) and ofa rare earth metal salt, preferably a cerium salt, at low temperature[Imamoto et al. Tetrahedron Lett. 25, 4233 (1984)]. Thus, treatment ofthe acetylenic intermediate I with an alkylithium base at lowtemperature, followed by treatment with cerium chloride, and subsequentreaction with cyclohexanone derivative II, circumvents the undesiredelimination reactions, and produces the desired acetylenic couplingproduct of structure III below, in satisfactory yield. Compounds ofgeneral structure III are new compounds. ##STR4##

The acetylenic coupling intermediate of general structure III above canalso be prepared by a novel alternative condensation process, namely bythe coupling of a perhydrindene ketone of general structure Ia, above,with an acetylenic ring-A unit, of general structure IIa, below.##STR5## Acetylenic ring A-synthons of structure IIa, which are newcompounds, are prepared by reaction of a cyclohexanone derivative offormula II, above, with a metal acetylide, preferably cerium acetylide,according to the general procedure described above for the condensationof acetylenic intermediate I with ketone II. In compounds of formulaIIa, X₁ X₂ and X₄, which may be the same or different, representhydrogen or a hydroxy-protecting group. For X₁ and X₂, preferredhydroxy-protecting groups are the silyl and alkoxyalkyl groups, whereasfor X₄, the preferred groupings include silyl, alkoxyalkyl, andespecially also C₁₋₆ alkyl groups as previously defined. The couplingbetween ketone Ia and acetylenic intermediate IIa is effected byconverting IIa to the corresponding metal acetylide (e.g. lithiumacetylide, or the magnesium haloacetylide) by treatment of IIa with astrong base (e.g. an alkyl lithium, or alkyl lithium aide or similarbase, or a alkyl Grignard reagent) in an ether or hydrocarbon solvent atlow temperature. Subsequent reaction of this acetylide with theC/D-ketone of general structure Ia, then provides the acetyleniccoupling product III, shown above. Alternatively, this coupling reactionmay also be conducted in the presence of rare earth metal salts such ascerium salts as described for the reaction between acetylene I andcyclohexanone II, above.

In compound III, as obtained by the condensation of aeetylenicderivative I with the cyclohexanone derivative II, the groups X₁, X₂ andX₃ represent hydroxy-protecting groups as originally present in theketone and aeetylenic derivative, respectively, whereas X₄ is hydrogen.When compound III is obtained by the coupling of a perhydrindene ketoneof general structure Ia with a ring-A acetylenic derivative of formulaIIa, the groups X₁ X₂ and X₄ in III represent hydroxy-protecting groupsas originally present in acetylene IIa, whereas X₃ is hydrogen.

The free hydroxy group in compound III can, however, also be protected,if desired, by any desired hydroxy-protecting group. For example,compound III, where X₄ =H, can be alkylated by known methods, to yieldthe derivative where X₄ =alkyl (e.g. methyl, ethyl, propyl, etc.), or itcan be silylated or alkoxyalkylated to derivatives where X₄ representsany of the silyl or alkoxyalkyl-protecting groups referred to above.Alternatively, if desired, one or more of the originally presenthydroxy-protecting groups (X₁, X₂, X₃) in compound III may be removed byknown methods to yield derivatives of III where one or more of X₁, X₂,X₃ represent hydrogen. For example, compound III, where X₁, X₂, X₃represent alkylsilyl groups and X₄ is hydrogen, can be hydrolyzed byknown methods to obtain the compound where all of X₁, X₂, X₃ and X₄represent hydrogen. Likewise, if compound III is obtained such that, forexample, X₁ and X₂ represent silyl groups, X₃ is alkyl and X₄ ishydrogen, it can be hydrolyzed under known conditions to the partiallydeprotected compound III, where X₁, X₂ and X₄ are hydrogen and X₃ isalkyl. Also, derivatives of compound III, e.g. where X₁, X₂ and X₃ aresilyl or alkoxyalkyl groups and X₄ is alkyl can be hydrolyzed to obtaina product where X₁, X₂, and X₃ represent hydrogen and X₄ is alkyl, andany free hydroxy groups in such a product can, of course, also bereprotected to obtain, for example, the derivative of structure III,where X₁ and X₂ represent silyl or alkoxyalkyl groups, X₃ is hydrogen,and X₄ is alkyl. Thus, it is obvious that by suitable choice ofprotecting groups in the A-ring and C/D-ring starting materials(subjected to the coupling reaction) and by optional subsequentprotection or deprotection reactions or combinations thereof,intermediate III can be obtained as the free tetraol or in any desiredpartially or completely hydroxy-protected form. In general, derivativesof compound III, where X₁ and X₂, independently, represent hydrogen or ahydroxy-protecting group selected from alkoxyalkyl or silyl, and whereX₃ and X₄, independently represent hydrogen or a hydroxy-protectinggroup selected from alkoxylalkyl, silyl or alkyl are suitable for thesubsequent steps of the process. Preferred derivatives are the compoundswhere X₁ and X₂ are both hydrogen, and where X₃ and X₄ are both hydrogenor both alkyl, or where one of X₃ and X₄ is hydrogen, the other alkyl.

The next step of the process comprises the partial reduction of the6,7-triple bond in compound III to obtain the corresponding 6,7-olefiniccompound, characterized by general structure IV below. ##STR6##Depending on the reduction conditions employed, the product IV obtainedin this step may have either the 6,7-cis or the 6,7-trans double bondconfiguration. Thus, reduction of compound III (where each of X₁, X₂,X₃, X₄, which may be the same or different, represent hydrogen or ahydroxy-protecting group as defined above) with hydrogen in the presenceof palladium catalyst yields the 6,7-cis product IVa (where each of X₁,X₂, X₃, X₄ may represent hydrogen or a hydrox-protecting group).##STR7## Alternatively, compound III may be reduced with hydridereducing agents in an organic solvent (e.g. LiAlH₄, etc., in an ethersolvent) to obtain the 6,7-trans-ene product characterized by structureIVb, below (where X₁, X₂, X₃, X₄ represent hydrogen orhydroxy-protecting groups as previously defined). ##STR8## Products oftype IVa or IVb are new compounds, and both of these intermediates aresuitable for further conversion to the desired final product.

Intermediate IV, as obtained above (i.e. either the 6,7-cis isomer IVaor the corresponding trans-isomer IVb) is then subjected to a furtherreduction step, using a low-valent titanium reducing agent of the typeemployed in the work of Walborsky and Wust, supra. Thus, treatment ofintermediate IV (where each of X₁, X₂, X₃, X₄, independently, representhydrogen or a hydroxy-protecting group and where the double bondconfiguration may be cis or trans) with mixtures of titanium chlorideand a metal hydride in an organic solvent yields the 5,7-diene productof general structure V (where X₁ and X₂ represent independently hydrogenor hydroxy-protecting groups as defined for the precursor III) as amixture of 7,8-cis and 7,8-trans-double bond stereoisomers. ##STR9##

It has also been found that product V (as a mixture of the 7,8-cis andtrans isomers) can be obtained in a single step from the acetyleniccoupling intermediate III by reaction with a metal hydride/titaniumreducing agent. For example, direct treatment of III with the low-valenttitanium reagent prepared by reacting a metal hydride with titaniumchloride provides the 5,7-diene product V as a mixture of 7,8-cis and7,8-trans-stereoisomers. Thus, the conversion of III to V can beaccomplished by the two alternative two-step procedures described above,as well as this one-step method. Best yields have been obtained with thetwo-step sequence involving catalytic hydrogenation, followed byreduction with metal hydride/titanium reagent.

The mixture of 7,8-cis- and 7,8-trans-isomers may be separated bychromatography (preferably high performance liquid chromatography) toobtain separately the 7,8-trans-isomers, i.e. the known 1α-hydroxy-19-nor-vitamin D compounds characterized by structure Va and the7,8-cis-isomer, represented by structure Vb, wherein X₁ and representhydrogen or hydroxy-protecting groups. ##STR10## The 7,8-cis-isomers ofgeneral structure Vb are new compounds. Any hydroxy-protecting groupspresent in compounds Va or Vb can, of course, be removed by conventionalmethods to obtain the corresponding free hydroxy compounds, i.e. Va andVb where both X₁ and X₂ represent hydrogen.

The 7,8-cis-isomers of general structure Vb can also serve as usefulintermediates for the production of the 7,8-trans compounds of structureVa. It has been found that treatment of the cis-isomer Vb with a thiolreagent (e.g. thiophenol) isomerizes the 7,8-cis double bond to yieldthe corresponding 7,8-trans isomer Va. This isomerization reaction canbe performed on isolated 7,8-cis-isomer, but preferably, especially whenthe 7,8-trans isomer Va is desired as the sole final product of thepresent process, the isomerization is performed directly on the originalmixture of the 7,8-cis- and 7,8-trans-isomers. Thus treatment of theintermediate product mixture V (where X₁ and X₂, independently,represent hydrogen or hydroxy-protecting groups) as obtained from thetitanium reduction step, with a thiol in an organic solvent yieldsspecifically the 7,8-trans-isomer Va. Any hydroxy-protecting groups, ifpresent, can then be removed by conventional methods to obtain1α-hydroxy- 19-nor-vitamin D product (compound Va, where X₁ and X₂represent hydrogen). The above described isomerization reaction usingthiol reagents is essentially quantitative, and provides a convenientmethod for the conversion of 7,8-cis-isomers of the vitamin D series totheir (generally desired) 7,8-trans-isomeric forms.

The side chain group R in any of the above-shown structures, i.e. instructures I, III, IV, and V may represent any of the presently knownsteroid side chain types. More specifically R can represent a saturatedor unsaturated hydrocarbon radical of 1 to 35 carbons, that may bestraight-chain, branched or cyclic and that may contain one or moreadditional substituents, such as hydroxy- or protected-hydroxy groups,fluoro, carbonyl, ester, epoxy, amino or other heteroatomic groups.Preferred side chains of this type are represented by the structurebelow. ##STR11## where the stereochemical center (corresponding to C-20in steroid numbering) may have the R or S configuration, (i.e. eitherthe natural configuration about carbon 20 or the 20-epi configuration),and where Z is selected from the group consisting of Y, --OY, --CH₂ OY,--C.tbd.CY and --CH═CHY, where the double bond may have the cis or transgeometry, and where Y is selected from the group consisting of hydrogen,methyl, --CR⁵ O and a radical of the structure, ##STR12## where m and n,independently, represent the integers from 0 to 5, where R¹ is selectedfrom the group consisting of hydrogen, hydroxy, protected hydroxy,fluoro, trifluoromethyl, and C₁₋₅ -alkyl, which may be straight chain orbranched and, optionally, bear a hydroxy or protected-hydroxysubstituent, and where each of R², R³, and R⁴, independently, isselected from the group consisting of hydrogen, fluoro, trifluoromethyland C₁₋₅ alkyl, which may be straight-chain or branched, and optionally,bear a hydroxy or protected-hydroxy substituent, and where R¹ and R₂,taken together, represent an oxo group, or an alkylidene group, ═CR² R³,or the group --(CH₂)_(p) --, where p is an integer from 2 to 5, andwhere R³ and R⁴, taken together, represent an oxo group, or the group--(CH₂)_(q) --, where q is an integer from 2 to 5, and where R⁵represents hydrogen, hydroxy, protected hydroxy, or C₁₋₅ alkyl.

A "protected hydroxy" group is a hydroxy group protected by any groupcommonly used for the temporary or permanent protection of hydroxyfunctions, e.g. the silyl, alkoxyalkyl, or alkyl groups, as previouslydefined.

Specific embodiments of the reactions of the new process are presentedin the following Examples. Process Scheme 1 depicts the structures ofthe compounds described in these Examples, such that products identifiedby Arabic numerals (e.g. 1, 2, 3, 3a, etc.) correspond to the structuresso numbered in the Process Scheme. The abbreviation "TBS" signifies at-butyldimethylsilyl hydroxy-protecting group.

EXAMPLES Example 1

Preparation of Acetylenic 5,8-Diol Intermediate, Compound 3

Cerium chloride (275 mg: 1.1 mmol) was dried with stirring at 140° C. invacuo (0.01 torr) for 2 h and cooled, dry tetrahydrofurane (3 ml) wasadded with stirring under argon and stirring was continued for 2 h. Theresulting suspension was then cooled to -78° C. and CD-ring lithiumacetylide [prepared by addition of 0.56M BuLi (1.98 ml) to a THFsolution (340 mg, 1.1 mmol) of CD ring acetylene (compound 1) at roomtemperature (RT)] was added. The color of the suspension turned yellow;stirring was continued for 30 rain at the same temperature. Then3,5-trans-dihydroxychclohexanone compound 2 (200 mg, 0.55 mmol) intetrahydrofuran (3 ml) was added. The mixture was stirred for 15 min,treated with sat. aqueous solution of NH₄ Cl and extracted with ether(3×50 ml). The combined extracts were washed with brine (20 ml), driedover MgSo₄, concentrated in vacuo and the residue was purithed by flashchromatography on silica gel to give 322 mg, 87%, of product 3. NMR ¹ H(CDCl₃), δ ppm, 0.05, 0.06, 0.07 (TBS-Me), 0.84 (26, 27, 21, 18 Me),0.87 (s, TBS-Me), 1.72 (dd, J=14.49 Hz, J=2.22 Hz, 1H), 1.90 (d, J=12.62Hz, 1H), 1.99 (d, J=12.66 Hz, 1H), 2.10 (d, J=14.3 Hz, 1H), 2.18 (d,J=14.14 Hz, 1H), 2.35 (d, m, J=13.25 Hz, 1H), 3.24 (s, 3H, OMe), 4.22(ddd, J=14.66 Hz, J=9.33 Hz, J=4.0 Hz, 1H, H-3), 4.28 (1s, 1H, H-1),4.58 (s, 1H, OH). MS: m/e (relative intensity), 662 (M⁺, 14%), 644(28%), 630 (27%), 605 (5%), 301 (20%), 143 (53%), 75 (100%).

Example 2

Hydrolysis of 3 to 3a

To a solution of 3 (81.5 mg; 0.12 mmol) in THF (4 ml) was added HF 48%(0.5 ml). The mixture was stirred at RT for 30 min, neutralized withsaturated solution of sodium bicarbonate and extracted with CH₂ Cl₂(3×20 ml). Combined organic layer was dried over MgSo₄ and concentrated.The product, compound 3 was used without further purification for thenext reaction.

¹ H NMR (CDCl₃) δ ppm: 0.84, 0.85, 0.86 (3s, 12H), 2.15 (m, 3H), 2.32(dm, J=9.97 Hz, 1H), 2.89 (1s, 1H), 3.24 (s, 3H), 4.21 (m, 1H), 4.27 (m,1H).

Example 4

Catalytic Hydrogenation of 3a to 4a

To a solution of triol of 3a (53 mg, 0.12 mmol) in MeOH (4 ml) was addedquinoline (11.5 μl, 0.09 mmol) and Lindlar catalyst (57 mg=0.02 mmol),stirred under a hydrogen atmosphere at RT for 45 min. The reactionmixture was filtered over celite using ethylacetate for washing.Purification on silica-gel using EtoAc/hexane (4:1) gives 48.11 mg ofpure product compound 4a. Yield from 3a, 90%.

¹ H NMR (CDCl₃) δ ppm: 0.83, 0.84, 0.86, 0.87 (4s, 12H), 1.97 (dm,J=13.74 Hz, 2H), 2.09 (dm, J=14.67 Hz, 1H), 2.20 (dm, J=14.67 Hz, 1H),2.29 (dm, J=12.83 Hz, 1H), 3.27 (s, 3H, OMe), 4.14 (m, 1H), 4.36 (m,1H), 4.75 (d, J=9.69 Hz, 1H), 4.90 (d, J=13.5 Hz, 1H), 5.20 (d, J=13.55Hz, 1H), 7.11 (s, 1H, OH). MS: m/e (relative intensity): 436 (M⁺, 18%),418 (9%), 404 (48%), 361 (100%), 345 (15%), 302 (15%), 247 (11%), 195(12%), 147 (13%), 95 (18%), 81 (19%), 55 (27%), 43 (45%).

Example 5

1α-Hydroxy-7(E&Z)-19-nor-vitamin D₃ 5a and 5b.

To a solution of TiCl₃ (268 mg, 1.73 mmol) in dry THF (1.4 ml) underargon was added 1M solution of LAH in ether (0.68 ml, 0.68 mmol) at RT,a black suspension formed, stirred for 30 min. Then a solution of triol4a (16 mg; 0.036 mmol) in THF (0.7 ml) was added, heated at reflux for 3h, cooled to RT, then hydrolyzed slowly with cold 1M HCl (10 ml). Themixture was extracted with ether (1×20 ml) and CH₂ Cl₂ (2×20 ml).Combined organic layers were washed with saturated solution of sodiumbicarbonate (10 ml), dried over MgSo₄ and concentrated. to obtain5,7-diene compound 5a and 5b (2:3). This product was used for theisomerization reaction without further purification.

¹ H NMR: (CDCl₃), δ: 0.52, 0.62 (2s, 3H, 18-Me), 0.85 (2d, J=6.77 Hz,J=5.25 Hz, 6H), 0.9 and 0.91 (2d, J=6.14 Hz, 5.1 Hz, 3H), 2.72 & 2.75 (2dm, J=9.32 Hz & J=10.33 Hz, 1H), 4.03 (m, 1H), 4.09 (m, 1H), 5.83 and6.09 (2d, J=11.19 Hz and J=11.3 Hz, 1H), 6.29 and 6.46 (2d, J=11.22 Hzand J=11.63 Hz, 1H).

Example 6

Isomerization of 5b to 5a

To the product (mixture of 5a/5b) as obtained in Example 5 was added CH₂Cl₂ (8 ml) and thiophenol (1 μl, 0.0097 mmol) at RT, stirred for 1 h.The isomerization was monitored by HPLC [reversed phase, MeOH:water(9:1)]. Complete isomerization is observed after 1 h. Solvent wasremoved under vacuum at RT, then silica gel chromatography usingEtoAc:hexane (4:1) gives 5a; yield=75% from 4a

¹ H NMR (CDCl₃) δ ppm: 0.52 (s, 3H, 18-Me), 0.85 (d, J=6.50 Hz, 6H,26,27-Me), 0.90 (d, J=6.05 Hz, 3H, 20-Me), 2.19 (m, 2H), 2.46 (dm,J=13.27 Hz, 1H), 2.72 (dd, J=13.17 Hz, J=3.60 Hz, 1H), 2.78 (dm, J=12.85Hz, 1H), 4.02 (m, 1H), 4.10 (m, 1H), 5.83 (d, J=10.98 Hz, 1H), 6.29 (d,J=11.2 Hz, 1H).

MS: m/e (relative intensity): 388 (M⁺, 100%), 275 (33%), 247 (30%), 180(21%), 133 (38%), 95 (52%), 81 (43), 55(46%), 43 (81%).

UV EtOH λ_(max) : 261 (21000), 251.1 (31000), 242.6 (26000).

Example 7

Hydride Reduction of 3a to 4b

To a solution of acetylchic alcohol 3a (24.7 mg, 0.059 mmol) in ether (1ml) at 0° C. was added 1M solution of LAH in THF (262 μl, 0.26 mmol).The mixture stirred at 0° C. for 1 h, quenched with 1M HCl (10 ml) andextracted with ether (3×10 ml). Combined organic layers were washed withbrine (5 ml), dried over MgSO₄ and concentrated to yield product 4b. ¹ HNMR (CDCl₃) δ ppm, 0.85 (26,27,21,18-Me), 3.24 (s, 3H), 4.21 (m, 1H),4.27 (m, 1H), 5.51 (2d, AB system, J=15.5 Hz, 2H).

Example 8

1α-Hydroxy-7(E&Z)-19-Nor-Vitamin D₃ 5a and 5b from 4b.

A solution of TiCl₃ (109 mg, 0.707 mmol) in THF (2 ml) was treated with1M solution of LAH (353 μl, 0.35 mmol), a black suspension formed thatwas stirred for 30 min at RT. A solution of product 4b as obtained inExample 7 (.057 mmol) in THF (2 ml) was added, stirred at RT for 30 min,then refluxed for 1 h, cooled to RT for 5 more h, quenched with 1M HCl(10 ml), extracted with ether (2×30 ml). Combined organic layers werewashed with water (10 ml) and brine (10 ml), dried over MgSo₄ andconcentrated under vacuum. Silica gel chromatography of residue usingMeOH/CH₂ Cl₂ (1:9) gave 3.63 mg of mixture of dienes 5a (and 5b); (16%)from 3a.

¹ H NMR (300 MHz) (CDCl₃) δ ppm: 0.52, 0.62 (2S,3H, 18-Me), 0.85 (d,J=6.45, 6H), 0.9 (m, 3H), 2.72, 2.75 (m, 1H), 4.03 (m, 1H), 4.09 (m,1H), 5.83 and 6.09 (2d, J=11.2 Hz, J=11.3 Hz, 1H), 6.29 and 6.45 (2d,J=11.2 and J=11.3 Hz, 1H).

Example 9

1α-Hydroxy-7(E&Z)-19-Nor-Vitamin D₃ 5a and 5b from 3a

A solution of TiCl₃ (266 mg, 1.73 mmol) in THF (5 ml) was treated at RTwith 1M solution of LAH in THF (860 μl, 0.86 mmol) for 30 min. To theresulting black suspension was added at 0° C. triol of 3a (53 mg, 0.123mmol) in THF (3 ml). The mixture was refluxed for 8 h, cooled to RT,stirred for 12 h, then quenched with 1N HCl (50 ml) and extracted withCH₂ Cl₂ (3×50 ml). Organic layers were combined, washed with saturatedsolution of NaHCo₃ (20 ml), brine (20 ml), dried over MgSo₄ andconcentrated under vacuum. Silica gel TLC preparative chromatography ofresidue gave 8.25 mg of mixture of 5a and 5b (17%).

¹ H NMR 500 MHz (CDCl₃), δ ppm: 0.52, 0.62 (2S,3H, 18-Me), 0.85 (2d,J=6.8 Hz and J=5.2 Hz, 6H), 0.9 and 0.91 (2d, J=6.14 Hz, J=5.1 Hz, 3H),2.72, 2.75 (2dm, J=9.32 Hz & J=10.33 Hz, 1H), 4.03 (m, 1H), 4.09 (m,1H), 5.83 and 6.09 (2d, J=11.04 Hz and J=11.61 Hz, 1H), 6.29 and 6.46(2d, J=11.12 Hz, J=11.56 Hz, 1H).

Example 10

Catalytic Hydrogenation of 3 to 4c

To a solution of compound 3 (7 mg, 0.01 mmol) in MeOH (0.3 ml)was addedquinoline (1 μl, 0.007 mmol) and Lindlar catalyst (1.1 mg, 0.0005 mmol),stirred under hydrogen atmosphere at room temperature for 15 hr. Thereaction mixture was filtered over celite and concentrated. Purificationof residue on silica gel using ethylacetate:hexane (5:95) gave 4.77 mgof pure 4, yield 68%.

¹ H NMR (CDCl₃ δ ppm, 0.02, 0.03, 0.08 (TBS-Me), 1.82 (m, 1H), 1.92 (m,1H), 2.11 (m, 1H), 3.21 (s, 3H), 4.14 (m, 1H), 4.20 (m, 1H), 4.91 (d,J=14.22 Hz, 1H), 5.65 (d, J=14.19 Hz, 1H), 6.02 (1s, 1H). ##STR13##

We claim:
 1. A compound of the formula:where X₁, and X₂ each represent,independently, hydrogen or a hydroxy-protecting group, and where R isrepresented by the structure ##STR14## where the stereochemical centerat carbon 20 in the side chain may have the R or S configuration, andwhere Z is selected from the group consisting of Y, --OY, --CH₂ OY,--C.tbd.CY and --CH═CHY, where the double bond may have the cis or transstereochemical configuration, and where Y is selected from the groupconsisting of hydrogen, methyl, --CR⁵ O and a radical of the structure,##STR15## where m and n, independently, represent the integers from 0 to5, where R¹ is selected from the group consisting of hydrogen, hydroxy,protected hydroxy, fluoro, trifluoromethyl, and C₁₋₅ -alkyl, which maybe straight chain or branched and, optionally bear a hydroxy orprotected-hydroxy substituent, and where each of R², R³, and R⁴,independently, is selected from the group consisting of hydrogen,fluoro, trifluoromethyl and C₁₋₅ alkyl, which may be straight-chain orbranched, and optionally, bear a hydroxy or protected-hydroxysubstituent, and where R¹ and R², taken together, represent an oxogroup, or an alkylidene group, ═CR² R³, or the group --(CH₂)_(p) --,where p is an integer from 2 to 5, and where R³ and R⁴, taken together,represent an oxo group, or the group --(CH₂)_(q) --, where q is aninteger from 2 to 5, and where R⁵ represents hydrogen, hydroxy,protected hydroxy, or C₁₋₅ alkyl.
 2. The compound of claim 1 where R isa side chain of the formula: ##STR16## and X₁ and X₂ are hydrogen. 3.The compound of claim 1 where R is a side chain of the formula:##STR17## and X₁ and X₂ are hydroxy-protecting groups.
 4. The compoundof claim 1 where R is a side chain of the formula: ##STR18## and X₁ andX₂ are hydroxy-protecting groups.
 5. The compound of claim 1 where R isa side chain of the formula: ##STR19## and X₁ and X₂ are hydrogen. 6.The compound of claim 1 where R is a side chain of the formula:##STR20## and X₁ and X₂ are hydrogen.